Prion proteins are epigenetic elements capable of adopting self-perpetuating conformations that are heritable, thereby producing traits based on protein structure rather than nucleic acid-based genes. While some prions are known to form pathological fibrous aggregates, increasing evidence suggests that prions-which are widespread in eukaryotes-have diverse roles in normal biological processes, and implicates them as important drivers of evolutionary change. In this proposal I will investigate how newly discovered prion proteins that normally regulate nucleic acid impact cell physiology when in the prion state. Yeast is the chosen model system for these studies, due to its genetic tractability and the high degree of similarity of protein aggregation mechanisms among eukaryotes. First, I will investigate how the prion-like behavior of a DNA repair enzyme may directly influence genomic integrity, through genetic and molecular analyses. My chosen example also has clearly defined links to human cancers. The remainder of the proposal will focus on prion proteins that regulate mRNA stability and translation, through a combination of genome-wide assays and molecular analyses. I expect that the impact of this work and my thorough training plan will both position me well to establish my own research group in the future.